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Thursday, September 22, 2011

Johnson and Johnson Pleads Guilty - a Reminder of the "Lost Decade" of Nesiritide

It was just a short article in Bloomberg about yet another misstep by Johnson and Johnson....

Johnson & Johnson (JNJ)’s Scios unit agreed to pay an $85 million fine and plead guilty to misbranding the heart drug Natrecor, the U.S. said.

Scios was charged in July with misbranding the medicine because its labeling lacked adequate directions for use. Under a plea agreement reached after months of negotiation with prosecutors, Scios will be placed under organizational probation for three years in addition to paying the fine....

Although the case did involve a guilty plea, the fine actually seemed small compared to some others we have seen lately. The article made it sound like this was just a technical mis-step in labeling.

A Darker History

However, another brief paragraph hinted at a more complex background:

Natrecor, given intravenously, was one of the first drugs for congestive heart failure when it was approved in 2001, and in 2004 it generated $230 million in revenue. Sales plummeted to less than $100 million in 2006 after reviews of its use in less than 1,000 patients tied the medicine to worsening kidney function and higher death rates.

Of course, to a physician, the first sentence makes no sense. Digitalis was probably the first effective drug for heart failure, and its use was described in the 18th century. To the rest we should pay heed.

A Lack of Evidence for Benefit Outweighing Harm

In fact, in 2005, Dr Eric Topol wrote a commentary in the New England Journal that discussed Natrecor's (nesiritide's) troubled history.(1)

Here are the main points:
- Nesiritide was first tested on seriously ill, hospitalized patients with congestive heart failure.
- The drug improved one measure of physiogic function, the pulmonary capillary web pressure. However, patients given nesiritide had a not statistically significant increase in mortality, and a later significant decrease in kidney function.
- Nesiritide was thus only approved for short-term use in acutely ill heart failure patients (in 2001).
- However, its manufacturer, Scios, a Johnson and Johnson subsidiary, vigorously promoted it for out-patient "tune ups," a use for which there was no evidence that its benefits outweighed its harms.
- This use, however, was very lucrative for the company at a price of $500 per dose. So,

outpatient nesiritide use has become widespread, fulfilling sales objectives for the manufacturer and bringing in revenue for physicians. The overall sales figure for nesiritide is projected to be $700 million for 2005, nearly double last year's tally; it represents payment for more than 1.4 million treatments. Given that nearly 10 times as much drug is used for serial administration in outpatients as for the one-time use in hospitalized patients, much of this growth clearly stems from the off-label 'tune-up' application.

At that time, Dr Topol summarized the case thus:

The nesiritide story reflects some recurring themes: in other recent cases, too, major safety problems have been uncovered after a drug has been approved. Nesiritide was approved on the basis of a single trial in which surrogate end points were assessed three hours after administration. In cardiovascular medicine, we learned long ago that therapies directed at surrogate end points — such as the suppression of premature ventricular contractions or, for inotropic agents, an improved ejection fraction — can be associated with excess deaths. With the low threshold set for regulatory approval, the FDA did not demand appropriate warnings on the label regarding an increased risk of death or worsened renal function and did not require the performance of trials that would have provided definitive verification of the safety and efficacy of nesiritide.

We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which companies will stretch the limits in their marketing of drugs. The boundary lines that previously separated industry from the FDA and academia have unfortunately become blurred.

No Evidence of Benefit in 2011, the End of the "Lost Decade"
Finally, in 2011, a larger study of the drug appeared.(2) It did not show that nesiritide increased mortality at 30 days, but neither did it decrease it. Essentially, it showed that the drug had no clinically important advantage over standard therapy. In an accompanying commentary, Dr Topol used the nesiritide case as an example of a "lost decade" due to "deficient clinical development of certain pharmaceutical agents."(3)

The FDA, without a prospective plan or capability to force the sponsor to perform a fitting trial after approval, unwittingly created a monster. Physicians, who prescribed nesiritide without definitive knowledge of efficacy or safety, particularly for off-label use such as for tune-up clinics, were treating patients without an adequate evidence base. The manufacturer in this case was the chief culprit because it widely promoted nesiritide in the early years after its approval but was unwilling to appropriate the resources to design and execute a compelling trial.

Summary
The sorry nesiritide case now seems to be staggering towards its conclusion with little fanfare (although the Bloomberg article noted that the legal proceedings related to it are not over. There is a pending civil False Claims suit brought by the US Department of Justice.)

So, 10 years after the drug was widely marketed to patients for whom it would do no good, the "chief culprit" has had a pay a small financial price, relative to the revenue it received, for an offense tangential to the lost decade created for patients and physicians who thought that nesiritide might be worth using. As usual in such cases, no individual who authorized, directed or implemented the "monster" that was the dubious nesiritide marketing campaign has suffered any negative consequences.

This was just the latest in a long series of legal misadventures by the once revered Johnson and Johnson. Its most recent guilty plea for a marketing offense was only a month ago (see post here.) That blog post listed five other recent adverse legal results related to the company's marketing.

Of course, as long as the company's leaders seem immune to any sort of negative consequences for its bad behavior, and as long as its board seems happy to pay millions to the executives who preside over these messes, why should the bad behavior stop? Do we expect multi-millionaire executives to actually worry about the ethics and morals of what they are doing? - not in an era when "greed is good," at least until the whole economy collapses from the aggregated greed of its leaders.

For physicians, the nesiritide case should remind us not to deploy a test or treatment without good evidence that it actually does patients more good than harm, even if we really hope it does, and even if the company that markets it really hopes so too.

For all of us, the case should remind us that if there are short-term monetary rewards but no penalties for unethical behavior, unethical behavior will continue.References

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